Buprenorphine is a semi-synthetic thebaine derivative which acts as a partial μ-opioid receptor agonist and κ-opioid receptor antagonist—an opioid. Opioid receptors are found principally in the central nervous system and the gastrointestinal tract. As a result of the partial agonist activity of buprenorphine at μ-opioid receptors, buprenorphine has a powerful analgesic effect—approximately twenty to forty times more potent as morphine.
Buprenorphine is available in various dosage forms, including sublingual and other oral formulations as well as parenteral dosage forms. The treatment of certain mammals, such as cats and dogs, with a sublingual medication that relies on continuous exposure to the oral mucosa of the mammal's mouth can be difficult to administer, resulting in poor pain control for the mammal. In addition, parenteral dosage forms may be given to mammals by several different routes of administration. Specifically, buprenorphine may be administered intravenously (“IV”) and intramuscularly (“IM”). The dosage varies depending on the route of administration. For example, when administered IV, the buprenorphine dose generally ranges from approximately 0.01-0.02 mg/kg of mammal body weight. See U. Krotscheck, D. V. M, D M Boothe D. V. M., and A A Little, D. V. M, Pharmacokinetics of buprenorphine following intravenous administration in dogs, AJVR, Vol. 69, No. 6, June 2008. Similarly, the dosing of buprenorphine for IM administration also ranges from approximately 0.01-0.02 mg/kg of mammal body weight. See L S Slingby, P M Taylor, and A E Waterman-Pearson, Effects of two doses of buprenorphine four or six hours apart on nociceptive thresholds, pain and sedation in dogs after castration, THE VETERINARY RECORD, Nov. 18, 2006, pp. 705-711; and S Dobbins, N O Brown, F S Shofer, Comparison of the Effects of Burprenorphine, Oxymorphone Hydrochloride, and Ketoprofen for Postoperative Analgesia After Onychectomy or Onychectomy and Sterilization in Cats; JOURNAL OF THE AMERICAN ANIMAL HOSPITAL ASSOCIATION; Vol. 38, November/December 2002, pp. 507-514. Subcutaneous (“SQ”) administration of buprenorphine has also been disclosed at doses up to approximately 0.02 mg/kg of mammal body weight. See P V Steagall et al., Effects of subcutaneous methadone, morphine, buprenorphine or saline on thermal and pressure thresholds in cats; JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS, 2006, Vol. 29, pp. 531-537.
Regardless of the route of administration, all forms of administration of buprenorphine are known to require dosing of the mammal every 2-8 hours for adequate pain control, depending on the route of administration and the pain threshold of the mammal. However, continuous administration of buprenorphine to the mammal by injection can be difficult to perform and stressful to the mammal, further complicating the pain control process. Companion animals, in particular, can be difficult to medicate, so analgesics that provide 24 hours of effect after a single dose would be advantageous. According to CVM-FDA policy, new veterinary pain medications are required to provide 72 hours of post-operative analgesia. Currently, no veterinary product is approved by CVM-FDA that will provide 24 hours of analgesia following a single injection, and can be administered for three consecutive days.
Additionally, the use of higher doses of buprenorphine would be expected to result in adverse effects to the mammal. Specifically, adverse effects associated with high dose buprenorphine include excessive sedation, respiratory depression, excessive salivation, and nausea. Due to the seriousness of such effects, commercially available buprenorphine products, such as the Vetergesic® buprenorphine injection, warns that dosing should not exceed to 10-20 micrograms per kg (0.01-0.02 mg/kg) for analgesia in dogs and cats, repeated if necessary after 2-6 hours.
Extended-release buprenorphine formulations have been developed to prolong the duration of pain control in a mammal. Injectable extended-release formulations, for example, include injectable microparticles, polymer matrix systems, fat emulsions, microspheres, and oil in water emulsions. However, the manufacturing of such formulations is complex and costly, and typically incorporates the use of organic solvents which could introduce potential toxicity if not completely removed. Additionally, it can be difficult to achieve sterility of microparticles and other oil solutions because terminal sterilization is not always possible. It is also difficult to appropriately control the release of a drug such as buprenorphine in an injectable dosage form in order to achieve the desired onset and duration of analgesic effects in the target species. Therefore, it would be desirable to have compositions and less complex methods of providing prolonged pain control to a mammal while minimizing the number of administrations/doses that must be given to the mammal.